Initial studies indicated that the male reproductive system is anatomically normal in mice with a targeted disruption in the ER gene (Lubahn et al., 1993). Although these studies indicated that male homozygous for the mutant ER gene (ERKO) had reduced fertility reanalysis of genotypes determined that the fertile mice were heterozygous for the mutation. We subsequently verified that male ERKO mice are sterile. Although reproductive organ weights and serum LH and FSH levels did not differ significantly between 4-6 month old ERKO and wild-type mice, testosterone levels were slightly elevated, sperm numbers and percent motility were reduced, testis weights were reduced, and mating was less frequent in ERKO than in wild-type males. There were no obvious histological differences between testes of ERKO and wild-type males at 10 days after birth, but at 20 days and thereafter thelumen of the seminiferous tubules were dilated in ERKO mice. There was subsequent degeneration of the tubules in ERKO mice, beginning at the caudal pole of the testis 70-90 days after birth, with degeneration occurring last in tubules at the cranial pole at 6-8 months of age. Our working hypothesis is that the dilation of the seminiferous tubules is caused by reduced reabsorption in the 5-8 efferent ducts that connect the testis to the epididymis. This is because approximately 90% of the fluid leaving the testis is reabsorbed in the efferent ductules by a sodium pump mechanism and they contain higher levels of ER than other male reproductive tract tissues.